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From Proteopedia
Mouse dCTPase in complex with 5-Me-dCMP
Structural highlights
Function[DCTP1_MOUSE] Hydrolyzes deoxynucleoside triphosphates (dNTPs) to the corresponding nucleoside monophosphates. Has a strong preference for modified dCTP. Activity is highest with 5-iodo-dCTP, followed by 5-bromo-dCTP, unmodified dCTP, 5-methyl-dCTP and 5-chloro-dCTP. Hydrolyzes 2-chloro-dATP and 2-hydroxy-dATP with lower efficiency, and has even lower activity with unmodified dATP, dTTP and dUTP (in vitro). Does not hydrolyze ATP, UTP, ITP, GTP, dADP, dCDP or dGTP. May protect DNA or RNA against the incorporation of non-canonical nucleotide triphosphates. May protect cells against inappropriate methylation of CpG islands by DNA methyltransferases.[1] [2] Publication Abstract from PubMedPrecise regulation of dNTPs within the cellular nucleotide pool is essential for high accuracy of DNA replication and is critical for retaining the genomic integrity. Recently, human dCTPase (deoxycytidine triphosphatase), also known as DCTPP1 (human all-alpha dCTP pyrophosphatase 1) has been revealed to be a key player in the balance of pyrimidine nucleotide concentrations within cells, with DCTPP1 deficiency causing DNA damage and genetic instability in both chromosomal and mitochondrial DNA. DCTPP1 also exhibits an additional 'house cleaning' function as it has been shown to be highly active against modified cytidine trinucleotides such as 5-methyl-dCTP, which if incorrectly incorporated into DNA can introduce undesirable epigenetic marking. To date, structural studies of mammalian dCTPase have been limited to inactive constructs, which do not provide information regarding the catalytic mechanism of this important enzyme. We here present the first structures of an active mammalian dCTPase from M. musculus in complex with the non-hydrolysable substrate analogue dCMPNPP and the products 5-Me-dCMP and dCMP. These structures provide clear insights into substrate binding and catalysis, and clearly elucidate why previous structures of mammalian dCTPase were catalytically inactive. The overall structure of M. musculus dCTPase is highly similar to enzymes from the all-alpha NTP phosphohydrolase superfamily. Comparison of M. musculus dCTPase with homologues from a diverse range of mammals including humans, show that the residues which contribute to substrate recognition are entirely conserved, further supporting the importance of this enzyme in the protection of genomic integrity in mammalian cells. The first structure of an active mammalian dCTPase and its complexes with substrate analogues and products.,Scaletti E, Claesson M, Helleday T, Jemth AS, Stenmark P J Mol Biol. 2020 Jan 15. pii: S0022-2836(20)30024-3. doi:, 10.1016/j.jmb.2020.01.005. PMID:31954130[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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